Substituted 2-imidazolines and use thereof

ABSTRACT

The invention relates to novel substituted 2-imidazolines (I) having a lowering effect on blood glucose in mammals, to their preparation, to pharmaceutical compostions containing them and to their use. ##STR1##

This application claims the benefit of copending PCT Application No.PCT/DK90/00184, filed Jul. 12, 1990, designating the United States ofAmerica.

FIELD OF THE INVENTION

The present invention relates to novel substituted 2-imidazolines havinga lowering effect on blood glucose in mammals, to their preparation, topharmaceutical compositions containing them and to their use.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a widespread disease, and the diagnosis is basedupon elevated blood glucose levels.

There are at least two subtypes of the disease: type 1 or insulindependent diabetes mellitus, and type 2 non insulin dependent diabetesmellitus. Worldwide the number of diabetics is steadily increasing,especially in the group with type 2 diabetes, where up to 10% of theolder generation (>65 years of age) in the western hemisphere willsuffer from type 2 diabetes.

The separation of the two subclasses is based on pathophysiological andclinical findings. In type 1 diabetes the insulin producing β-cells inpancreas are destroyed by a selective auto immune reaction. The clinicaloutcome is due to the absolute insulin deficiency, and these patientswill die from the disease unless treated with insulin regularly.

The underlying pathophysiological mechanisms in type 2 diabetes are notfully clarified. The various tissues are less sensitive to insulin(insulin resistance). The β-cell function is partially preserved, andthe type 2 diabetic patients secrete enough insulin to be protected fromthe development of diabetic coma--eventually leading to exitus.

However, the insulin secretion pattern is altered in connection withmeals, as the increase is too slow and protracted and unable tonormalize the blood glucose profile. In more severe cases the β-cellfunction is also decreased in the fasting state, and fasting bloodglucose becomes elevated as well. The normal, complex regulation of theβ-cell function is disturbed in type 2 patients. This regulation includethe effect of different substrates (e.g. glucose, alanine), and hormones(e.g. glucagon), which may increase or decrease the insulin release.Furthermore the secretion is also regulated via α- and β-adrenergicnerve fibres. It is striking that especially glucose becomes lesseffective as an insulin-releasing agent in type 2 diabetics as thedisease becomes more severe.

According to current recommendations all type 2 patients are prescribeda diabetes diet, and some patients achieve acceptable blood glucoselevels on diet alone. However, the majority of patients needs some kindof medical treatment as well. The standard approach is to prescribe asulphonylurea, which will cause an increase in insulin secretion.Sulphonylureas are effective even at normal or low levels of bloodglucose. Therefore there is a considerable risk of the occurence ofsevere hypoglycaemia on sulphonylurea treatment, and even fatal caseshave been reported.

Good glycaemic control (i.e. constant blood glucose values near normallevels) is officially recommended as the only way to protect patientsfrom the diabetic micro- and macro-vascular complications, such asblindness, renal failure, acute myocardial infarction, gangrene, etc.However, many patients are reluctant to follow this strategy, as theyanticipate a higher number of severe hypoglycaemic attacks.

DESCRIPTION OF THE PRIOR ART

A method for treating diabetes comprising administering atherapeutically effective amount of2-[2-phenyl-2-(2-pyridyl)]ethyl-2-imidazoline is described in U.S. Pat.No. 4,138,491 (Daiichi Seiyaku Co., Ltd.). However the Daiichi patentcontains no mention of a moderate effect of the compounds when the bloodglucose is low and a stronger effect when the blood glucose is high.

Imidazoline derivatives wherein the 2-position of an otherwiseunsubstituted 2-imidazoline nucleus is linked to the 2-position of anoptionally substituted 2,3-dihydrobenzofuran are described in Europeanpatent application publication No. 71,368 (Reckitt and Colman Products,Ltd.). The compounds exhibit presynaptic α₂ -adrenoreceptor antagonistactivity, and in the specification it is mentioned that α₂-adrenoreceptor antagonists may have a role to play in the control ofdiabetes. However, the application has no claims directed to this useand no experimental results concerning this aspect are presented.

GB patent application publication No. 2,167,408 (Farmos Yhtyma OY)describes selective α₂ receptor antagonists. The compounds comprise anotherwise unsubstituted imidazole ring which through its 4(5)-positionis linked to a ring carbon atom in an optionally substituted ringsystem. In the application it is mentioned that α₂ receptor antagonistsmay be useful in the treatment of diabetes. However, the applicationcontains no experimental results or claims relating to this indication.

The present standard treatment of type 2 diabetes is far from optimal.The majority of the type 2 diabetic patients are not well controlled,which is demonstrated by the very high number of patients with severediabetic complications. Therefore new ways of treatment are urgentlyneeded.

SCOPE OF THE INVENTION

According to the present invention there are provided novel compoundswith a lowering effect on blood glucose in mammals including man.

The compounds according to the present invention are expected torepresent a major improvement of the present treatment of type 2diabetes, the predominant features of these novel compounds being:

1. A strong ability to decrease blood glucose when the initial level ishigh e.g. in connection with meals.

2. A much more subtle effect on blood glucose in the fasting state(relative inability to induce hypoglycaemia).

Thus it can be expected that the compounds of the invention will enablethe patient to achieve a good glycaemic control while at the same timethe risk of hypoglycaemic attacks is minimized.

SUMMARY OF THE INVENTION

In its broadest aspect the present invention comprises 2-imidazolineswhich via a two-linked carbon chain in the 2-position are linked to the2-, 5-, or 7-position of an optionally substituted benzofuran ring whichmay be partly saturated. The compounds according to the presentinvention thus have the general formula (I): ##STR2## wherein R¹ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or a bond tothe side chain carrying the imidazoline ring; R² is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or together with R³ represents anadditional bond; R³ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloroor bromo, phenyl, phenyl substituted by a substituent selected from thegroup consisting of fluoro, and chloro, C₁₋₄ alkyl (e.g. methyl), C₁₋₄alkoxy (e.g. methoxy) or together with R² represents an additional bond;R⁴ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro, bromo, phenyl,phenyl substituted by a substituent selected from the group consistingof fluoro, and chloro, C₁₋₄ alkyl (e.g. methyl), C₁₋₄ alkoxy (e.g.methoxy); R⁵ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, phenyl optionally substituted by methyl, methoxy,fluoro or chloro, or a bond to the side chain carrying the imidazolinering; R⁶ is phenyl optionally substituted by methyl, methoxy, fluoro orchloro, 2-pyridyl, 3-pyridyl or 4-pyridyl, preferably 2-pyridyl, eachpyridyl group optionally carrying a C₁₋₄ alkyl substituent (preferablymethyl); R⁷ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, phenyl, optionally substituted by methyl, methoxy, fluoro,chloro or R⁷ is a bond to the side chain carrying the imidazoline ring.When R² and R³ do not together represent an additional bond and R¹ andR² are different from each other and/or R⁴ and R³ are different fromeach other the compounds of formula (I) exist in stereoisomeric ordiastereoisomeric forms. The carbon atom to which R⁶ is linked isassymmetric thus giving rise to optical isomers. All these isomericforms and mixtures thereof are within the scope of the invention as arethe pharmaceutically acceptable acid addition salts of the compounds offormula (I).

In a first group of preferred compounds according to the invention R¹ isa bond to the side chain carrying the imidazoline ring.

In a second group of preferred compounds according to the invention R¹is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, or C₁₋₄ alkoxy, morepreferred R¹ is hydrogen or C₁₋₄ alkyl.

In a further group of preferred compounds according to the invention R²together with R³ represents an additional bond.

In a further group of preferred compounds according to the invention R²is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, or C₁₋₄ alkoxy, morepreferred R² is hydrogen or C₁₋₄ alkyl.

In a further group of preferred compounds according to the invention R³is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyloptionally substituted by a substituent selected from the groupconsisting of fluoro, chloro, C₁₋₄ alkyl (e.g. methyl), and C₁₋₄ alkoxy(e.g. methoxy), more preferred R³ is hydrogen or C₁₋₄ alkyl.

In a further group of preferred compounds according to the invention R⁴is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro, bromo, phenyloptionally substituted by a substituent selected from the groupconsisting of fluoro, chloro, C₁₋₄ alkyl (e.g. methyl), and C₁₋₄ alkoxy(e.g. methoxy), more preferred R⁴ is hydrogen or C₁₋₄ alkyl.

In a further group of preferred compounds according to the invention R⁵is a bond to the side chain carrying the imidazoline ring.

In a further group of preferred compounds according to the invention R⁵is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, orphenyl optionally substituted by a substituent selected from the groupconsisting of methyl, methoxy, fluoro or chloro, more preferred R⁵ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, or C₁₋₄ alkoxy.

In a further group of preferred compounds according to the invention R⁶is phenyl optionally substituted by methyl, fluoro or chloro.

In a further group of preferred compounds according to the invention R⁶is 2-pyridyl, 3-pyridyl or 4-pyridyl, preferably 2-pyridyl.

In a further group of preferred compounds according to the invention R⁶is 2-pyridyl, 3-pyridyl or 4-pyridyl, in each case substituted by a C₁₋₄alkyl substituent, preferably methyl.

In a further group of preferred compounds according to the invention R⁷is a bond to the side chain carrying the imidazoline ring.

In a further group of preferred compounds according to the invention R⁷is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, orphenyl optionally substituted by a substituent selected from the groupconsisting of methyl, methoxy, fluoro, or chloro, more preferred R⁷ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, or C₁₋₄ alkoxy.

The compounds of the present invention can be prepared according to themethods outlined in the following description of preparation methodsA-F.

DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS Preparation Method A

The compounds of the formula (II) of the present invention are preparedas outlined in scheme A. ##STR3##

Step 1. A substituted 7-benzofuran carboxylic acid wherein R¹,R²,R³,R⁴and R⁵ are as defined above (R¹ and R⁵ are not a bond to the side chaincarrying the imidazoline ring) is transformed into the correspondingnitrile. First, the acid is transformed into an acid chloride by knownmethods. While an inert solvent may be employed it is generallypreferred to use an excess of the chlorinating agent as a solvent inorder to dispense with the use of further solvents.

Generally the reaction mixture is heated to at least 60° C. The acidchloride is transformed into the corresponding amide by reacting it witha ammonium hydroxide solution. The amide is isolated using knowntechniques.

In order to form the nitrile the amide is reacted with a dehydratingagent such as oxalyl chloride or thionyl chloride. Generally thereaction mixture is heated to at least 70° C. for 1 hour and later to90° C. for 4 to 18 hours. The nitrile is isolated using known techniquesand recrystallized from an alcohol (methanol, ethanol, propanol,2-propanol, tert-butanol).

Step 2. The substituted 7-cyano-benzofuran from Step 1 is transformedinto the ketone wherein R¹,R²,R³,R⁴,R⁵ and R⁶ are as defined above. Inthis step the nitrile is reacted with 2-lithium pyridin to form a iminewhich is hydrolysed with an acid to the corresponding ketone. The ketoneis isolated using known techniques and recrystallized (if a solid) froman alcohol (methanol, ethanol, 2-propanol or tert-butanol). In analternative method wherein R¹, R²,R³,R⁴ and R⁵ are as defined above thenitrile is reacted with a Grignard reagent to form a imine which ishydrolysed to the corresponding ketone. The Grignard reagent is preparedby known methods.

Step 3. The 3,3-disubstituted acrylic acid derivatives whereinR¹,R²,R³,R⁴,R⁵ and R⁶ are as defined above, are prepared from theketones by reacting them with the corresponding disubstitutedphosphonoacetic acid derivatives (X and R⁷ as defined above) underWebb's modified Wittig-Horner condition (Webb et al. synthesis 122(1974) ). The reaction is carried out at from -10° C. to the refluxtemperature of the reaction mixture and is generally complete in from 3to 24 hours. It is preferred to carry out the reaction at from aboutroom temperature to 40° C. The product is isolated using techniquesknown to those skilled in the art with the product generally not beingpurified but rather used directly in the next step.

Step 4. The olefinic products serve as intermediates for preparation ofthe corresponding reduced 3,3-disubstituted propionic acid derivativeswherein R¹,R²,R³,R⁴,R⁵,R⁶,X and R⁷ are as defined above. While thereduction of the above olefinic compounds can be carried out byemploying a number of reducing agents which are known to reducecarbon-to-carbon double bonds, the preferred methods employ hydrogen inthe presence of a nobel metal catalyst (e.g. palladium on carbon) orsodium amalgam in an suitable solvent. An especially preferred solventis ethanol. Hydrogen at from 1 to 4 atmospheres is employed and thereaction is complete in from 4 to 24 hours. Room temperature ispreferred, however, an elevated temperature of up to 50° C. may beemployed. The product is isolated using standard techniques. If desired,purification is done by well known methods such as crystallization or bychromatography.

Step 5. The propionic acid derivatives are used to prepare thecorresponding 2-imidazolines (II) wherein R¹,R²,R³,R⁴,R⁵,R⁶ and R⁷ areas defined above. Conventional preparation of 2-imidazolines normallyrequires nitriles or imino ethers as starting materials. Only inselected cases can carboxylic acid ester be reacted directly withethylenediamine to give 2-imidazolines. Drastic reaction conditions(sealed tube, 160°-300° C. and Mg as an catalyst) often limit theusefulness of these procedures. A bifunctional unit such as1,2-diaminoethane is effectively coupled with trimethylaluminum toproduce reagents that are treated with a carboxylic acid ester to give2-imidazolines. The reaction is carried out at from -10° to 0° C. Thecarboxylic acid ester is normally added dissolved in the solvent ofchoice. The reaction is carried out at reflux temperature of thereaction mixture and is generally compleat in from 4 to 12 hours. Theproduct is isolated using techniques known to those skilled in the artwith the product generally being purified by well known methods such ascrystallization and/or chromatography.

Preparation Method B

The compounds of the formula (III) of the present invention are preparedas outlined in scheme B. ##STR4##

Step 1. 2,3-Dihydrobenzofuran is transformed into the ketone wherein R⁶is as defined above. In this step 2,3-dihydrobenzofuran is treated witha lithium base to form 2,3-dihydro-7-lithium-benzofuran which is reactedwith a 2-cyano pyridine to form a imine which is hydrolysed with an acidto the corresponding ketone. Temperature is not very critical, but willgenerally be from -5° C. to the reflux temperature of the reactionmixture. To the lithium reagent, at the temperature interval mentioned,is added the nitrile mentioned above. The imine is hydrolysed to theketone by known methods. The ketone is isolated using known techniquesand recrystallized from an alcohol (methanol, ethanol, 2-propanol,tert-butanol).

Step 2. As Step 3 in preparation method A. R¹,R²,R³,R⁴,R⁵ are H.

Step 3. As Step 4 in preparation method A. R¹,R²,R³,R⁴,R⁵ are H.

Step 4. As Step 5 in preparation method A. R¹,R²,R³,R⁴,R⁵ are H.

Preparation Method C

The compounds of the formula (IV) of the present invention are preparedas outlined in scheme C.

Step 1. Bromination of 2,3-Dihydrobenzofuran gives5-bromo-2,3-dihydrobenzofuran which serves as an intermediate for theketone in scheme C step 2. Bromination of 2,3-dihydrobenzofuran isperformed by conventional means. 2,3-dihydrobenzofuran is normallybrominated by adding 1 equivalent of bromine to a solution of2,3-dihydrobenzofuran in an appropriate solvent. The reaction is carriedout at from 0° C. to 25° C. and is generally complete in 3 hours. Theproduct is isolated using techniques known to those skilled in the art.Purification, if desired, is performed by distillation. ##STR5##

Step 2. 5-Bromo-2,3-dihydro-benzofuran is transformed into the ketonewherein R⁶ is as defined above. In this step a cyano pyridine is reactedwith 2,3-dihydrobenzofuran-5-magnesium-bromide to form an imine which ishydrolysed to the corresponding ketone. The Grignard reagent is preparedby known methods. The imine is hydrolysed to the ketone by knownmethods. The ketone is isolated using known techniques andrecrystallized (if solid) from an alcohol (methanol, ethanol,2-propanol, tert-butanol).

Step 3. As Step 3 in preparation method A. R¹,R²,R³,R⁴,R⁷ are H.

Step 4. As Step 4 in preparation method A. R¹,R²,R³,R⁴,R⁷ are H.

Step 5. As Step 5 in preparation method A. R¹,R²,R³,R⁴,R⁷ are H

Preparation Method D

The compounds of the formula (V) of the present invention are preparedas outlined in scheme D.

Starting material (Formula D) for preparation of the compounds of theformula (V), wherein the imidazoline side chain is positioned inposition 2 of the benzofuran nucleus, is described in literature (F.Binon et al., Chimie Therapeutique 2, 113 (1967) and J. Chem. Soc. 3693(1955)). ##STR6##

When R⁶ is as defined above the benzofuran nucleus can be substituted invarious positions with halogen (chlorine, bromine), alkyl (preferablymethyl) and alkyloxy (preferably methoxy). ##STR7##

Step 1. As Step 3 in preparation method A.

Step 2. As Step 4 in preparation method A.

Step 3. As Step 5 in preparation method A.

Preparation Method E

The compounds of the formula (VI) of the present invention are preparedas outline in scheme E.

Step 1. An appropriate 5-halogen benzofuran, (preferably5-chloro-benzofuran) is transformed into the corresponding7-bromo-5-halogen-2,3-dihydrobenzofuran wherein R⁶ is as defined aboveand R⁵ is halogen (fluoro, chloro or bromo). In this step, selectivereduction of the 2,3-double bond in the benzofuran nucleus gives2,3-dihydrobenzofurans which by selective bromination give7-bromo-5-halogen-2,3-dihydrobenzofuran. While reduction of5-halogen-benzofuran can be carried out by employing a number ofreducing agents which are known to reduce carbon-to-carbon double bonds,the preferred methods employ hydrogen in the presence of a nobel metalcatalyst (preferably rhodium on carbon). When the reduction is carriedout employing hydrogen in the presence of a nobel metal catalyst, aconvenient method for carrying out this transformation is to stir orshake a solution of the 5-halogen-benzofuran compound under anatmosphere of hydrogen, in the presence of a noble metal hydrogenationcatalyst. Suitable solvents for this reaction are those whichsubstantially dissolve the starting compound but which do not themselvessuffer hydrogenation or hydrogenolysis. Examples of such solventsinclude alcohols such as methanol and ethanol and the like; ethers suchas diethyl ether, tetrahydrofuran and the like. An especially preferredsolvent is ethanol. Room temperature is preferred, however, an elevatedtemperature of up to 50° C. may be employed. The product is isolatedusing standard techniques. ##STR8##

If desired, purification is performed by well known methods such ascrystallization or chromatography.

5-halogen-2,3-dihydrobenzofuran is brominated to yield7-bromo-5-halogen-2,3-dihydrobenzofuran as described in preparationmethod C step 1. The product is isolated using standard techniques. Ifdesired, purification is performed by well known methods such asdistillation or crystallization.

Step 2. 7-bromo-5-halogen-2,3-dihydro-benzofuran is transformed into aketone wherein R⁵ and R⁶ are as defined above. In this step a cyanopyridine is reacted with5-halogen-2,3-dihydrobenzofuran-7-magnesiumbromide to form an iminewhich is hydroysed to the corresponding ketone. The Grignard reagent isprepared by known methods.

In an alternative method wherein R⁵ and R⁶ are as defined above7-bromo-5-halogen-2,3-dihydrobenzofuran is treated with a lithium baseto form 5-halogen-2,3-dihydro-7-lithium-benzofuran which is reacted witha cyano pyridine to form an imine which is hydrolysed with an acid togive the corresponding ketone. The imine is hydrolysed to the ketone byknown methods. The ketone is isolated using known techniques andrecrystallized (if solid) from an alcohol (methanol, ethanol, propanol,2-propanol or tert-butanol), preferably ethanol.

Step 3. As Step 3 in preparation method A. R¹,R²,R³ and R⁴ are H.

Step 4. As Step 4 in preparation method A. Preferred is a nobel metalcatalyst such as rhodium on carbon. R¹,R²,R³ and R⁴ are H.

Step 5. As Step 5 in preparation method A. R¹,R²,R³ and R⁴ are H.

Preparation Method F

The compounds of the formula (VII) of the present invention are preparedas outlined in scheme F. ##STR9##

Step 1. An appropriately substituted 5-methoxybenzofuran-7-carboxylicacid is transformed into the ketone wherein R ,R²,R³,R⁴ and R⁶ are asdefined above with the proviso that R¹ cannot be a bond to the sidechain carrying the imidazoline ring. In the first step, the acid istransformed into an acid chloride by reaction with a chlorinating agentsuch as phosphorus oxychloride or thionyl chloride. The5-methoxybenzofuran-7-carbonyl chloride wherein R¹,R²,R³,R⁴ and R⁶ areas defined above is reacted with 2-trimethylsilyl pyridine to form aketone. The solvent employed is generally a solvent compatible with thereaction condition and it is thus generally preferred to use dimethylformamide. It is generally preferred to add a base in order to speed upthe reaction and preferred as a base is a sterically hindered alkoxidebase such as potassium tert-butoxide. Room temperature is preferred,however, an elevated temperature of up to 50° C. may be employed.

In an alternative method wherein R⁶ is as defined above the5-methoxybenzofuran-7-carbonyl chloride is transformed by known methodsinto the corresponding symmetric anhydride which is reacted with2-trimethylsilyl pyridine to form the ketone as described above. Anelevated temperature of up to 100° C. may be employed. The ketone isisolated using known techniques and recrystallized (if solid) from analcohol (methanol, ethanol, 2-propanol or tert-butanol), preferablyethanol.

Step 2. As Step 3 in preparation method A. R¹,R²,R³,R⁴ as defined above,R⁵ is methoxy.

Step 3. As Step 4 in preparation method A. R¹,R²,R³,R⁴ as defined above,R⁵ is methoxy.

Step 4. As Step 5 in preparation method A. R¹, R²,R³,R⁴ as definedabove, R⁵ is methoxy.

Pharmacological Test Results

The compounds were tested in 200-250 g male Wistar rats, which wereeither fed or fasted overnight. The animals were anaesthesized with abarbital injection i.p. and a catheter was placed in the internalcarotid artery. The animals received either a 10 mg/kg i.v. injection ofone of the compounds of the invention or a control injection of saline.

The findings are summarized in table 1 and 2 and expressed as meanvalues.

                  Table 1                                                         ______________________________________                                        Blood glucose (mmol/1) after administration of                                compound (7), (27), and (32) to normal rats                                   Min. Compound                                                                 after                                                                              (7)         (27)        (32)      control                                adm. fasted  fed     fasted                                                                              fed   fasted                                                                              fed   fed                              ______________________________________                                         0   6.7     10.3    6.8   10.6  6.5   10.4  9.5                               5   6.3     9.7     6.5   10.7  6.3   10.4  9.5                              10   5.9     8.8     6.3   9.7   5.7   8.9   9.3                              20   5.1     7.1     6.0   7.6   5.1   7.6   8.8                              30   4.9     6.3     5.5   7.3   4.7   7.7   8.9                              45   5.2     7.0     5.5   8.3   4.5   8.2   9.7                              ______________________________________                                    

Thus, the compounds were significantly more effective duringhyperglycaemia than during euglycaemia (Max. Δ-glucoe: (7): 4.0 vs. 1.8mmol/l; (27): 3.3 vs. 1.3 mmol/l; (32): 2.8 vs. 2.0 mmol/l). All valueswere well above the limits for hypoglycaeumia (>3 mmol/l).

                  TABLE 2                                                         ______________________________________                                        Insulin levels (pmol/l) after i.v. administration of                          10 mg/kg bodyweight to normal rats (fasted or fed)                            Compound                                                                              Plasma insulin                                                        Min.                             Con-                                         after   (7)        (27)       (32)     trol                                   adm.    fasted  fed    fasted                                                                              fed  fasted                                                                              fed  fed                              ______________________________________                                         0      133     165    137   320  100   120  234                               5      204     623    255   493  262   345  284                              10      177     327    287   403  192   489  223                              20      202     396    282   233  154   265  195                              30      165     297    212   168  106   143  218                              45      122     172    140   115  85    109  300                              ______________________________________                                    

It can be noticed that the compounds caused a much more pronouncedincrease in insulin secretion in fed rats than in fasted rats.

The activity of the compounds is probably related to their insulinreleasing properties (table 2).

Pharmaceutical Compositions

For use in the treatment of type 2 diabetes the compounds of the presentinvention will generally be available in the form of pharmaceuticalcompositions. Such compositions may be in the form of powders,solutions, or suspensions, which may or may not be divided in singledose units, or in the form of capsules or tablets.

The pharmaceutical compositions may comprise carriers, diluents,absorption enhancers and other ingredients which are conventionally usedin the art.

The route of administration may be any route which effectivelytransports the active compound to its site of action, the oral or nasalroute being preferred.

The daily dose to be administered in therapy will be determined by aphysician and will depend on the specific compound employed and on theage and the condition of the patient.

EXAMPLES

The carboxylic acids required as starting materials in the synthesis ofthe imidazoline derivatives are known from the chemical literature e.g.from British patent applications Nos. 23,888/69, 42,763/69, and57,434/69 (all to NOVO TERAPEUTISK LABORATORIUM A/S). 5-chlorobenzofuranis described in Indian Academy of Sciences, 338 (1963).

The following examples illustrate the present invention morespecifically; however, it should be understood that these examples aregiven to explain the invention and not to limit the scope of theinvention.

EXAMPLE 1 Preparation of2-[2-[7-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(7), using preparation method A 2,3-dihydro-7-benzofuran carbonyl amide(2)

A mixture of SOCl₂ (8 ml, 109.64 mmol) in dry THF (10 ml) was addeddropwise to a stirred solution of 2,3-dihydro-7-benzofuranylcarboxylicacid (1) (12 g, 73.10 mmol) in dry THF (150 ml) under N₂. The reactionmixture was heated to 60° C. for 2 h. After cooling the reaction mixturewas added dropwise to an ice cooled vigorously stirred ammoniumhydroxide solution (500 ml 25% NH3) maintaining the temperature below 5°C. The reaction mixture was stirred at room temperature for 1 h.,concentrated in vacuo, and the residue was extracted with CH₂ Cl₂ (3×100ml). The extracts were washed with water (2×60 ml), brine (50 ml), dried(Na₂ SO₄) and evaporated to yield a solid which was recrystallized fromtoluene (300 ml) to give (2) as a white solid (10.17 g, 85%).

Mp. 187°-187.8° C.

1H-NMR (80 MHz, CDCl₃) δ 7.87 (d, 1H, J=7.47 Hz), 7.35 (bs, 1H, CONH₂),7.29 (d, 1H, J=6.93 Hz), 6.9 (t, 1H), 6.07 (bs, 1H, CONH₂), 4.68 (t,2H), 3.23 (t, 2H).

    ______________________________________                                        C.sub.9 H.sub.9 NO.sub.2                                                                  % C          % H    % N                                           ______________________________________                                        Calculated  66.24        5.57   8.59                                          Found       66.67        5.70   8.46                                          ______________________________________                                    

7-cyano-2,3-dihydro-benzofuran (3)

To a suspension of (2) (10 g, 61.28 mmol) i dry toluene (50 ml) wasadded SOCl₂ (12 ml, 164.92 mmol) under N₂. The reaction mixture washeated to 70° C. for 1 h. and then to 90° C. until TLC (AcOEt/Heptane1:1) indicated complete reaction Water (20 ml) was slowly added to theice cooled reaction mixture followed by 50% KOH until pH≈8. The organiclayer was separated, and the aqueous layer was extracted with toluene(3×50 ml). The combined organic layers were washed with water (2×30 ml),brine (1×30 ml), dried (Na₂ SO₄), and evaporated in vacuo to yield (3)as a solid (8.81 g, 99%). Recrystallization from abs. EtOH gave (3) as awhite solid.

Mp. 54.5°-56° C.

¹ H-NMR (80 MHz, CDCl₃) δ 7.3 (dd, 2H, H₄ +H₆), 6.82 (t, 1H, H₅), 4.7(t, 2H), 3.24 (t, 2H).

    ______________________________________                                        C.sub.9 H.sub.7 NO                                                                        % C          % H    % N                                           ______________________________________                                        Calculated  74.46        4.87   9.65                                          Found       74.66        4.87   9.55                                          ______________________________________                                    

2-pyridyl-[7-(2,3-dihydrobenzofuranyl)]ketone (4)

Dry ether (70 ml) was placed under a N₂ atmosphere in a flame driedflask. The flask was cooled to -65° C., and a solution of BuLi in hexane(20.28 ml, 72.74 mmol) was added. To the resulting solution was slowlyadded a solution of 2-Bromopyridine (7.15 ml, 72.74 mmol) in dry ether(20 ml) maintaining the temperature at -55° C. The colour changed todeep red. The solution was stirred for 15 min. and the a dry ether (50ml) solution of (3) (8.8 g, 60.62 mmol) was slowly added maintaining thetemperature at -50° C. The reaction mixture was heated to -40° C. anstirred for 1 h. and then 1 h. at room temperature. The reaction mixturewas poured into 5N HCl (150 ml) and heated to reflux for 2 h. Theorganic layer was separated, and the aqueous layer was washed(extracted) with ether (3×40 ml) made alkaline with 5N NaOH to pH≈8.5and extracted with CH₂ Cl₂ (3×70 ml). The CH₂ Cl₂ extracts were washedwith water (2×40 ml), brine (1×40 ml), dried (MgSO₄) and evaporated invacuo to yield 12.47 g of a brown solid. Recrystallization from abs.EtOH (80 ml) and ether (80 ml) gave 6.43 g of (4). Evaporation andrecrystallization of the mother liquid gave an other 918 mg a total of7.35 g 54% (4) was collected.

Mp. 127.5°-128.5° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.69 (d, 1H), 7.90 (d, 1H), 7.88 (t, 1H),7.57 (d, 1H), 7.54 (dd, 1H), 6.95 (t, 1H), 4.60 (t, 2H), 3.24 (t, 2H).

    ______________________________________                                        C.sub.14 H.sub.11 NO.sub.2                                                                % C          % H    % N                                           ______________________________________                                        Calculated  74.64        4.93   6.22                                          Found       74.96        4.89   6.17                                          ______________________________________                                    

Ethyl 3-[7-(2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)acrylate (5)

Sodium (920 mg, 40 mmol) was dissolved in dry EtOH (20 ml). The solutionwas cooled to -10° C. and a solution of triethyl phosphonoacetate (8.97g, 40 mmol) in dry EtOH (5 ml) was added maintaining the temperature at-5° C. The reaction mixture was allowed to reach 10° C. and stirred for15 min. (4) (6.40 g , 30 mmol) was added at -5° C. and the resultingmixture heated to 60° C. for 3 h. The bulk of the EtOH was evaporated,and the resulting mass was dissolved in CH₂ Cl₂ (100 ml) and washed withwater (3×30 ml), brine (1×20 ml), dried MgSO₄ and evaporated in vacuo toyield 8.86 g (100%) of (5) as a oil.

The Z- and E-isomers could be separated using chromatography(AcOEt/Heptane 1:1).

1. isomer Mp. 124.3°-125.2° C.

¹ H-NMR (80 MHz, CDCl₃) of the 1.-isomer δ 8.58 (d, 1H), 7.63 (t, 1H),7.17 (m, 2H), 6.90 (s, 1H), 6.62 (m, 2H, incl. the methine), 4.55 (t,2H), 3.97 (q, 2H), 3.14 (t, 2H), (1.04 (t, 3H).

2. isomer Mp. 73.5°-75° C.

¹ H-NMR (80 MHz, CDCl₃) of the 2.-isomer δ 8.60 (d, 1H), 7.53 (t, 1H),7.22-6.82 (m, 5H, incl. the methine), 4.45 (t, 2H), 4.05 (q, 2H), 3.19(t, 2H), 1.12 (t, 3H).

Ethyl 3-[7-(2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)propionate (6)

(5) (4.6 g, 15.57 mmol) in dry EtOH (200 ml) was hydrogenated over 10%Pd/C (2 g) catalyst in room temperature under atomospheric pressure.When H₂ absorption ceased the catalyst was filtered off and the filtratewas concentrated in vacuo to give 4.08 g (88%) of (6) as a colourlessoil.

¹ H-NMR (80 MHz, CDCl₃) δ 8.48 (d, 1H), 7.50 (t, 1H), 7.13-6.63 (m, 5H),4.83 (dd, 1H, CH--CH₂), 4.50 (t, 2H), 4.00 (q, 2H), 3.42 (dd, 1H,CH--CH₂), 3.13 (t, 2H), 2.95 (dd, 1H, CH--CH₂), 1.07 (t, 3H).

2-[2-[7-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline (7)

Trimethylaluminum (12.35 ml, 24.70 mmol, 2.0 M in toluene) was placedunder a N₂ atmosphere in a flame dried flask. Ethylenediamine (1.66 ml,24.70 mmol) was added at -10° C. and the mixture was stirred at roomtemperature until the methane evolution ceased. A solution of (6) (4.59g, 15.44 mmol) in dry toluene was added and the resulting mixture washeated to reflux for 4 h. The reaction was quenched at 0° C. with amixture of water (25 ml), MeOH (90 ml) and CH₂ Cl₂ (90 ml). Theresulting mixture was refluxed for 15 min., filtered through Na₂ SO₄ (3cm) and evaporated in vacuo, yielding a foam 5.5 g. The foam wasdissolved in AcOEt (60 ml) and refluxed for 30 min. to remove traces ofaluminum hydroxide from the crude product. Filtration of the hotsolution over Na₂ SO₄ (2 cm) and removal of the solvent in vacuo, gavecrude (7) (4 g, 88%). Analytically pure samples were obtained bykugelrohr distillation and recrystallization from acetone.

Mp. 144.5°-145.7° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.54 (d, 1H), 7.54 (t, 1H), 7.25 (d, 1H),7.10 (t, 1H), 7.02 (dd, 2H), 6.76 (t, 1H), 4.73 (dd, 1H, CH--CH₂), 4.55(t, 2H), 3.60 (bs, 4H, CH₂ --CH₂), 3.31 (dd, 1H, CH--CH₂), 3.19 (t, 2H),2.96 (dd, 1H, CH--CH₂).

    ______________________________________                                        C.sub.18 H.sub.19 N.sub.3 O                                                               % C          % H    % N                                           ______________________________________                                        Calculated  73.68        6.54   14.33                                         Found       73.67        6.67   14.00                                         ______________________________________                                    

EXAMPLE 2 Preparation of2-[2-[7-(2,3-dihydrobenzofuranyl)]-2-(4-fluorophenyl)ethyl]-2-imidazoline,(11), using preparation method A4-fluorophenyl-[7-(2,3-dihydrobenzofuranyl)]ketone (8)

To a solution of 2,3-dihydro-7-cyanobenzofuran, (3) (3 g, 20.67 mmol) indry THF (80 ml) was added a solution of 4-fluorophenylmagnesium bromide(≈41.33 mmol) in dry THF (25 ml). The resulting mixture was refluxed for4.5 h. cooled to -5° C., 5N HCl (150 ml) was added and the mixtureextracted with CH₂ Cl₂ (2×80 ml). To the resulting water phase was addedtoluene (80 ml) and the mixture heated to reflux for 4 h. The layer wasseparated and the water layer was extracted with toluene (3×50 ml). Thecombined organic layers were washed with water (30 ml), brine (30 ml),dried MgSO₄ and evaporated in vacuo, yielding (8) (3.84 g, 77%) as greencrystals. Recrystallization from EtOH (30 ml) gave (8) as whitecrystals.

Mp. 120.5°-121.7° C.

¹ H-NMR (80 MHz, CDCl₃) δ 7.83 (m, 2H), 7.37 (m, 5H), 4.55 (t, 2H), 3.19(t, 2H).

Ethyl 3-[7-(2,3-dihydrobenzofuranyl).-3-(4-fluorophenyl)acrylate (9)

Sodium (560 mg, 24.35 mmol) was dissolved in dry EtOH (20 ml). Thesolution was cooled to -10° C. and a solution oftriethylphosphonoacetate (4.45 ml, 22.41 mmol) in dry EtOH (6 ml) wasadded maintaining the temperature at -5° C. The reaction mixture wasallowed to reach 10° C. and stirred for 15 min. (8) was added at -5° C.and the resulting mixture heated to 60° C. for 18 h. The bulk of theEtOH was evaporated, and the resulting mass was dissolved in CH₂ Cl₂(100 ml) and washed with water (3×30 m1), brine (1×20 ml), dried MgSO₄and evaporated in vacuo to yield 5.99 g of (9) as a bright tea colouredoil, which was used without further purification.

¹ H-NMR (80 MHz, CDCl₃) δ 7.40-6.63 (m, 7H), (6.83 for E and 6.30 for Z(2 s, 1H), 4.53 (m, 2H), 4.05 (m, 2H), 3.20 (t, 2H), 1.18 (m, 3H).

Ethyl 3-7-(2,3-dihydrobenzofuranyl)]-3-(4-fluorophenyl)propionate (10)

(10) Was prepared in a way similar to the one described for (6). Thecrude product was purified by chromatography (toluene) yielding (10)(88% from (8) ) as a oil.

¹ H-NMR (80 MHz, CDCl₃) δ 7.25 (m, 2H), 6.87 (m, 5H), 4.57 (m, H), 3.97(q, 2H), 3.09 (m, 4H), 1.07 (t, 3H).

2-[2-7-(2,3-dihydrobenzofuranyl)]-2-(4-fluorophenyl)1-ethyl-2-imidazoline(11)

(11) was prepared in a way similar to the one described for (7).

Mp. 107.5°-108.5° C.

¹ H-NMR (80 MHz, CDCl₃) 7.22 (m, 2H), 6.88 (m, 5H), 4.48 (t, 2H, O--CH₂--CH₂), 3.65 (bs, 1H, NH), 3.38 (s, 4H, CH₂ --CH₂), 3.03 (t, 2H, O--CH₂--CH₂).

    ______________________________________                                        C.sub.19 H.sub.19 N.sub.2 FO.1/2 H.sub.2 O                                                    % C        % H    % N                                         ______________________________________                                        Calculated      71.44      6.32   8.77                                        Found           71.48      6.33   8.38                                        ______________________________________                                    

EXAMPLE 3 Preparation of2-[2-[7-(2,3,5-trimethyl-benzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(17), using preparation method A2,3,5-trimethyl-2,3-dihydro-7-benzofuran carbonyl amide (12)

(12) was prepared in a way similar to the one described for (2).

Mp. 158.5°-160.5° C.

¹ H-NMR (80 MHz, CDCl₃) δ 7.70 (s, 1H), 7.47 (bs, 1H, CONH₂), 7.02 (s,1H), 6.00 (bs, 1H, CONH₂), 5.00 (m) and 4.47 (m) (1H, pair ofdiastereomers) , 3.40 (m) and 3.07 (m) (1H, pair of diastereomers), 2.30(s, 3H), 1.53-1.13 (4 dd, 6H, could not be assigned)

7-cyano 2,3,5-trimethyl-2,3-dihydro-benzofuran (13)

(13) was prepared in a way similar to the one described for (3).

¹ H-NMR (80 MHz, CDCl₃) δ 7.02 (bs, 2H), 4.97 (m) and 4.45 (m) (1H, pairof diastereomers), 3.40 (m) and 3.10 (m) (1H, pair of diastereomers),2.21 (s, 3H), 1.48-1.07 (4 dd, 6H).

2-pyridyl-[7-(2,3,5-trimethyl-2,3-dihydrobenzofuranyl)]ketone (14)

(14) was prepared in a way similar to the one described for (4). (14)was purified by kugel rohr distillation (220° C., 0.2 mmHg) yielding(14) as a oil.

¹ H-NMR (80 MHz, CDCl₃) δ 8.63 (d, 1H), 8.03 - 7.07 (m, 5H), 4.82 (m)and 4.30 (m) (1H, pair of diastereomers), 3.33 (m) and 2.95 (m) (1H,pair of diastereomers), 2.26 (s, 3H), 1.37-1.12 (4 dd, 6H, could not beassigned).

Ethyl3-[7-(2,3,5-trimethyl-2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)acrylate(15)

(15) was prepared in a way similar to the one described for (9). (15)was isolated as a coloured oil, which was used without furtherpurification.

¹ H-NMR (80 MHz, CDCl₃) δ 8.60 (d, 1H), 7.77-6.83 (m, 5H), 6.60 and 6.40(2 s, 1H, C═CH), 4.83 (m) and 4.12 (m) (3H, O--CH(CH₃) and COO--CH₂--CH₃), 3.22 (m) and 2.95 (m) (1H, CH(CH₃)), 2.27 (s) and 2.12 (s) (3H,aromate-CH₃), 1.43-0.97 (m, 9H, O--CH(CH₃)--CH(CH₃), COO--CH₂ --CH₃).

Ethyl3-[7-(2,3,5-trimethyl-2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)propionate(16)

(16) was prepared in a way similar to the one described for (6). (16)was purified by chromatography (AcOEt/Heptane 1:3) yielding (16) as anoil.

¹ H-NMR (80 MHz, CDCl₃) δ 8.48 (d, 1H), 7.57-6.73 (m, 5H), 4.82 (m) and4.23 (m) (2H, CH--CH₂, O--CH--(CH₃)), 4.02 (q, 2H), 3.42 (m) and 2.95(m) (3H, CH--CH₂, O--CH(CH₃)--CH(CH₃)), 4.00 (q, 2H, CH--CH₂), 2.17 (s,3H), 1.42-0.98 (m, 9H, O--CH(CH₃)--CH(CH₃ ), COOCH₂ --CH₃)

2-[2-[7-(2,3,5-trimethyl-2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(17)

(17) was prepared in a way similar to the one described for (7) Thecrude product was purified by chromatography (Al₂ O₃, 5% EtOH in CH₂Cl₂). The product contains all six isomers. TLC (Al₂ O₃, 5% EtOH in CH₂Cl₂): one spot.

Mp. 110°-114° C.

¹ H-NMR (400 MHz, d₆ -acetone) δ 8.48 (d, 1H), 7.56 (t, 1H), 7.23 (dd,1H), 7.10 (t, 1H), 6.84 (bs, 1H), 6.77 (d, 1H), 4.81 (m, 1,5H, CH--CH₂,O--CH(CH₃)--CH), 4.28 (sextet, 0.5H, O--H(CH₃)--CH), 3.31 (m, 5.5H, CH₂--CH₂, CH--CH₂, O--CH(CH₃)--CH(CH₃)), 2.98 (sextet, 0.5H,O--CH(CH₃)--CH(CH)₃), 2.77 (dd, 1H, CH--CH₂), 2.16 (s, 3H, CH₃), 1,27(m, 3H, O--CH(CH₃)), 1.12 (m, 3H, O--CH(CH₃)--CH(CH₃)).

    ______________________________________                                        C.sub.21 H.sub.25 N.sub.3 O.1/2 H.sub.2 O                                                   % C        % H    % N                                           ______________________________________                                        Calculated    73.21      7.62   12.20                                         Found         73.53      7.71   12.08                                         ______________________________________                                    

EXAMPLE 4 Preparation of2-[2-[7-(2,2,5-trimethyl-2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(23), using preparation method A2,2,5-trimethyl-2,3-dihydro-7-benzofuran carbonyl amide (18)

(18) was prepared in a way similar to the one described for (2).

Recrystallized from heptane.

Mp. 129°-130° C.

¹ H-NMR (400 MHz, CDCl₃) δ 7.68 (s, 1H), 7.53 (bs, 1H), 7.06 (s, 1H),5.97 (bs, 1H), 3.02 (s, 2H), 2.30 (s, 3H), 1.52 (s, 3H).

7-cyano-2.2.5.trimethyl-2,3-dihydrobenzofuran (19)

(19) was prepared in a way similar to the one described for (3).

¹ H-NMR (400 MHz, CDCl₃) δ 7.11 (s, 1H), 7.06 (s, 1H) 2.99 (s, 2H), 2.25(s, 3H), 1.52 (s, 6H)

2-pyridyl-[7-(2,2,5-trimethyl-2,3-dihydrobenzofuranyl)]-hetone (20)

(20) was prepared in a way similar to the one described for (4). (20)was purified by chromatography (AcOEt/cyclohexane 1:2).

¹ H-NMR (400 MHz, CDCl₃) δ 8.63 (d, 1H), 7.89 (d, 1H), 7.81 (t, 1H),7.41 (dd, 1H), 7.33 (s, 1H), 7.11 (s, 1H), 2.94 (s, 2H), 2.30 (s, 3H),1.36 (s, 6H).

Ethyl3-[7-(2,2,5-trimethyl-2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)acrylate(21)

(21) was prepared in a way similar to the one described for (5).

¹ H-NMR (400 MHz, CDCl₃) δ 8.63 (t, 1H), 7.67 and 7.56 (two t, 1H),7.28-7.09 (m, 3H), 6.96 and 6.89 (two s, 2H), 6.71 and 6.42 (two s, 1H),4.07 and 4.00 (two q, 2H), 2.99 and 2.94 (two s, 2H), 2.26 and 2.12 (twos, 3H), 1.42 and 1.35 (two s, 6H), 1.15 and 1.09 (two t, 3H).

Ethyl3-[7-(2,2,5-trimethyl-2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)propionate(22)

(22) was prepared in a way similar to the one described for (6).

¹ H-NMR (400 MHz, CDCl₃) 8.50 (d, 1H), 7.50 (t, 1H), 7.23 (d, 1H), 7.04(t, 1H), 6.76 (ds, 2H), 4.79 (dd, 1H, CH--CH₂), 4.05 (q, 2H), 3.44 (dd,1H, CH--CH₂), 2.98 (dd, 1H, CH--CH₂), 2.93 (s, 2H), 2.19 (s, 3H), 1.41(s, 6H), 1,13 (t, 3H).

2-[2-[7-(2,2,5-trimethyl 2,3-dihydrobenzofuranyl)]-2-(2pyridyl)ethyl]-2-imidazoline (23)

(23) was prepared in a way similar to the one described for (7).

Mp. 80.3°-81.4° C.

¹ H-NMR (400 MHz, CDCl₃) 8.51 (d, 1H), 7.52 (dt, 1H), 7.26 (d, 1H), 7.07(t, 1H), 6.79 (ds, 2H), 4.66 (dd, 1H, CH--CH₂), 3.42 (bs, 4H, CH₂--CH₂), 3.32 (dd, 1H, CH--CH₂), 2.95 (dd, 1H, CH--CH₂), 2.93 (s, 2H),2.19 (s, 3H).

EXAMPLE 5 Preparation of2-[2-[7-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(7), using preparation method B 2-pyridyl-[7-(23-dihydrobenzofuranyl)]ketone (4)

2,3-dihydrobenzofuran (12.01 g, 100 mmol) was mixed with dry Bu₂ O (200ml). A mixture of BuLi (40 ml of a 2.5 M solution in hexane, 100 mmol)and dry Bu₂ O (50 ml) was added dropwise with stirring at 5°-10° C.,When the addition was completed the temperature of the mixture wasallowed to reach room temperature and the mixture was then immersed inan oil bath at 90° C. for 16 hours. The mixture was then cooled to 5° C.and a solution of 2-cyano-pyridine (10.41 g, 100 mmol) in dry Bu₂ O (50ml) was added dropwise. After stirring at room temperature for 60 hoursthe reaction mixture was hydrolysed with ice cold HCl, made alkalinewith NaOH and extracted with Et₂ O. The ether extract was dried over Na₂SO₄ and the ether was evaporated. The residue was chromatographed onsilica gel and the product was recrystallised from EtOH. Yield: 15 g(70%) of the desired intermediate.

Mp. 125°-6° C.

    ______________________________________                                        C.sub.14 H.sub.11 NO.sub.2                                                                % C          % H    % N                                           ______________________________________                                        Calculated  74.65        4.92   6.22                                          Found       74.80        4.93   6.21                                          ______________________________________                                    

Ethyl 3-[7-(2.3-dihydrobenzofuranyl)]-3-(2-pyridyl)-acrylate

Sodium (0.92 g, 40 mmol) was dissolved in dry EtOH (30 ml). At 5°-10° C.triethyl phosphonoacetate (8.97 g, 40 mmol) was added to the sodiumethanolate solution and the mixture was stirred at 5° C. for 10 minutes.(4) (30 mmol) was added to the cold solution of the Wittig reagent andthe mixture was allowed to reach room temperature. After stirring for 20hours the solvent was removed in vacuo. The residue was triturated withwater, the pH being adjusted to 7 with 4 N HCl, and this mixture wasextracted once with Et₂ O. The ether phase was discarded. The waterphase was made alkaline with 4 N aqueous NaOH and extracted with CH₂Cl₂. The extract was shaken with saturated aqueous NaCl and dried overNa₂ SO₄. The solvent was removed in vacuo to leave 8.86 g (100%) ofcrude product. TLC on silica gel (AcOEt/CH₂ Cl₂ 1:9) revealed two spotswhich were supposed to be the Z and E isomer respectively of the desiredcompound.

Ethyl 3-[7-(2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)-propionate (6)

(5) (5.9 g, 20 mmol, crude product) was dissolved in warm EtOH (70 ml,99%). The mixture was diluted with more EtOH (70 ml, 99%) and cooled toroom temperature. 10% palladium on carbon (300 mg) was added and themixture was hydrogenated at atmospheric pressure. The consumption ofhydrogen was 450 ml. The catalyst was filtered off and the filtrateevaporated to leave 5.65 g (95%) of crude product. After purification onsilica gel a yield of 4,76 g (80%) of the desired product was obtained.

2-[2-[7-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline (7)

(6) (2.97 g, 10 mmol, crude product) was mixed with ethylenediamine(6.01 g, 100 mmol (dried, redistilled)) and the mixture was refluxedunder N₂ for 24 hours. Water, EtOH and excess ethylenediamine was thendistilled off at atmospheric pressure under N₂. During the final stageof the distillation the temperature of the heating bath was raised to250° C. Still under N₂ the distillation flask was allowed to cool toroom temperature. Magnesium powder (0.24 g, 10 mmol) was added, and theheating of the flask was resumed, this time in a bath at 240° C., stillunder N₂. After 2 hours the contents of the flask were distilled at 0.1mmHg. The flask was heated to about 300° C. and distillate was collectedover the boiling point range 206°-216° C. The distillate crystallised oncooling and was recrystallised from acetone. Yield: 0.44 g of the titlecompound, (7).

Mp. 145.5°-146° C.

    ______________________________________                                        C.sub.18 H.sub.19 N.sub.3 O                                                               % C          % H    % N                                           ______________________________________                                        Calculated  73.69        6.53   14.32                                         Found       73.65        6.54   14.07                                         ______________________________________                                    

Analytical data in agreement with corresponding data from example 1.

EXAMPLE 6 Preparation of2-[2-[5-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(27), using a first version (cf. Example 7) of preparation method C2-pyridyl-[5-(2,3-dihydrobenzofuranyl]ketone (24)

2,3-dihydrobenzofuran-5-magnesiumbromide (85.61 g, 0.36 M) in dry THFwas added dropwise to a cooled solution (ice bath) of 2-cyano pyridine(28.21 g, 0.28 M) in dry THF (300 ml). The mixture was allowed to reachroom temperature and stirred for 24 h. Then hydrolysed (5 N HCl),basified (5 N NaOH), extracted with AcOEt (3×150 ml), dried (Na₂ SO₄)and evaporated to yield crude (24) which was purified by chromatography(10% AcOEt/Toluene) and recrystallized from Et₂ O. Yield 28.62 g 35%.

Mp. 67°-68° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.67 (d, 1H), 7.94 (t, 3H), 7.86 (dt, 1H),7.42 (m, 1H), 6.81 (d, 1H), 4.66 (t, 2H), 3.26 (t, 2H).

    ______________________________________                                        C.sub.14 H.sub.11 NO.sub.2                                                                % C          % H    % N                                           ______________________________________                                        Calculated  74.65        4.92   6.22                                          Found       74.93        4.98   6.08                                          ______________________________________                                    

3-[5-(2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)acrylonitrile (25)

Sodium (1.26 mg, 55 mmol) was dissolved in dry EtOH (50 ml). Thesolution was cooled to -10° C. and a solution of diethylcyanomethylphosphonate (9.41 g, 55 mmol) was added dropwise maintainingthe temperature at -5° C. The reaction mixture was allowed to reach 10°C. and stirred for 15 min. (24) (11.26 g, 50 mmol) was added at -5° C.and the resulting mixture heated to reflux for 16 h. The bulk of theEtOH was evaporated, and the resulting mass was dissolved in CH₂ Cl₂(150 ml) and washed with water (3×50 ml), brine (1×50 ml), dried Na₂ SO₄and evaporated in vacuo to yield crude (25).

(25) was purified using chromatography (AcOEt/Heptane 1:1) yield 8.69 g.

Mp. 74°-75° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.68 (d, 1H), 7.67 (dt, 1H), 7.34 (t, 2H),7.21 (t, 2H), 6.88 (d, 1H), 6.47 (s, 1H, methine), 4.66 (t, 2H), 3.28(t, 2H).

3-[5-(2,3-dihydrobenzofuranyl)]-3-(2-pyridyl)propionitrile (26)

(26) was prepared in a way similar to the one described for (6).

¹ H-NMR (400 MHz, CDCl₃) δ 8.60 (d, 1H), 7.60 (dt, 1H), 7.15 (m, 3H),7.03 (dd, 1H), 6.72 (d, 1H), 4.54 (t, 2H), 4.37 (t, 1H, CH--CH₂), 3.34(dd, 1H, CH--CH₂), 3.16 (t, 2H), 3.05 (dd, 1H, CH--CH₂).

2-[2-[5-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(27)

(26) (0.98 g, 3.90 mmol), was mixed with ethylene diamine (4 ml) andphosphorous pentasulfide (150 mg). The mixture was heated to 80° C. for20 h. To the cooled mixture was added EtOH/H₂ O 1:1 (50 ml) and themixture was stirred for 30 min. The mixture was extracted with CH₂ Cl₂(3×20 ml), dried (Na₂ SO₄) and evaporated in vacuo to yield crude (27)which was purified by chromatography (basic Al₂ O₃, 20% EtOH/CH₂ Cl₂).Yield 366 mg 32%.

Mp. 127°-128° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.54 (d, 1H), 7.54 (t, 1H), 7.14 (d, 2H),7.11 (t, 1H), 7.04 (d, 1H), 6.66 (d, 1H), 4.53 (t, 2H), 4.46 (t, 1H),3.42 (bs, 4H), 3.27 (dd, 1H), 3.15 (t, 2H), 2.88 (dd, 1H).

    ______________________________________                                        C.sub.18 H.sub.19 N.sub.3 O                                                               % C          % H    % N                                           ______________________________________                                        Calculated  73.68        6.54   14.33                                         Found       73.32        6.69   13.91                                         ______________________________________                                    

EXAMPLE 7 Preparation of2-[2-[5-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(27), using a second version (c.f. Example 6) of preparation method CEthyl 3-[5-(2,3-dihydrobenzofuranyl)-3-(2-pyridyl)-acrylate (28)

(28) was prepared in a way similar to the one described for (5). Thecrude product was used without further purification.

Ethyl 3-[5-(2,3-dihydrobenzofuranyl)-3-(2-pyridyl)-propionate (29)

(29) was prepared in a way similar to the one described for (6).

¹ H-NMR (400 MHz, CDCl₃) δ 8.58 (d, 1H), 7.58 (t, 1H), 7.18 (d, 2H),7.11 (dd, 1H), 7.07 (d, 1H), 6.70 (d, 1H), 4.54 (m, 3H), 4.06 (q, 2H),3.40 (dd, 1H), 3.16 (t, 2H), 2.26 (dd, 1H), 1.14 (t, 3H).

2-[2-[5-(2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(27)

(27) was prepared in a way similar to the one described for (7). (27)was purified by chromatography (Al₂ O₃, 10% EtOH in AcOEt).

Mp. 127.5°-128.4° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.53 (d, 1H), 7.56 (dt, 1H), 7.15 (d, 2H),7.11 (t, 1H), 7.05 (d, 1H), 6.67 (d, 1H), 4.50 (t, 2H), 4.44 (t, 1H,CH--CH₂), 3.43 (bs, 4H, CH₂ --CH₂), 3.27 (dd, 1H, CH--CH₂), 3.14 (t,2H), 2.88 (dd, 1H, CH--CH₂).

    ______________________________________                                        C.sub.18 H.sub.19 N.sub.3 O                                                               % C          % H    % N                                           ______________________________________                                        Calculated  73.68        6.54   14.33                                         Found       73.50        6.67   14.02                                         ______________________________________                                    

EXAMPLE 8 Preparation of2-[2-(2-benzofuranyl)-2-(2-pyridyl)ethyl]-2-imidazoline, (32), usingpreparation method D Ethyl 3-(2-benzofuranyl)-3-(2-pyridyl)acrylate (30)

(30) was prepared in a way similar to the one described for (5). Thecrude product was distilled and the fraction boiling at 198° C./0.05mmHg was collected. The product was recrystallized from Et₂ O. Yield 88%

Mp. 88°-89° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.67 (d, 1H), 7.68 (dt, 1H), 7.59 (d, 1H),7.45 (d, 1H), 7.33 (m, 3H), 7.25 (d, 1H), 7.02 (s, 1H), 6.90 (s, 1H),4.21 (q, 2H), 1.20 (t, 3H).

    ______________________________________                                        C.sub.18 H.sub.15 NO.sub.3                                                                % C          % H    % N                                           ______________________________________                                        Calculated  73.70        5.16   4.78                                          Found       73.89        5.20   4.63                                          ______________________________________                                    

Ethyl 3-(2-benzofuranyl)-3-(2-pyridyl)propionate (31)

(31) was prepared in a way similar to the one described for (6). Thecrude product was purified by chromatography (10% AcOEt in CH₂ Cl₂)Yield 90%.

¹ H-NMR (400 MHz, CDCl₃) δ 8.56 (d, 1H), 7.61 (dt, 1H), 7.45 (dd, 1H),7.38 (dd, 1H), 7.29 (d, 1H], 7.15 (m, 3H), 6.49 (s, 1H), 4.85 (t, 1H),4.09 (q, 2H), 3.38 (dd, 1H), 3.20 (dd, 1M), 1.17 (t, 3H).

2-[2-(2-benzofuranyl)-2-(2-pyridyl)ethyl-2-imidazoline (32)

(32) was prepared in a way similar to the one described for (7). Thecrude product was purified by chromathography (basic Al₂ O₃, 20% i-PrOHin AcOEt). Recrystallized from AcOEt. Yield 38%.

Mp. 109°-111.6° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.56 (d, 1H), 7.62 (dt, 1H), 7.48 (d, 1H),7.39 (d, 1H), 7.27 (d, 1H), 7.18 (m, 3H), 6.56 (s, 1H), 4.77 (t, 1H),3.47 (bs, 5H, NH, CH₂ --CH₂), 3.25 (dd, 1H), 3.16 (dd, 1H).

    ______________________________________                                        C.sub.18 H.sub.17 N.sub.3 O.H.sub.2 O                                                       % C        % H    % N                                           ______________________________________                                        Calculated    73.21      7.62   12.20                                         Found         73.53      7.71   12.08                                         ______________________________________                                    

EXAMPLE 9 Preparation of2-[2-[7-(5-chloro-2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(3s), using preparation method E 5-chloro-2,3-dihydrobenzofuran (33)

5-Chloro-benzofurane (2 g, 13.11 mmol) in dry EtOH (20 ml) washydrogenated over 10% Rh/C (251 mg) catalyst at room temperature underatmospheric pressure. When H₂ absorption ceased the catalyst wasfiltered off and the filtrate was concentrated in vacuo to give 1.84 g(91%) of (33) as a colourless solid. ¹ H-NMR (80 MHz, CDCl₃) δ 7.00 (d,2H, J=8.53 Hz), 6.62 (d, 1H, J=8.53), 4.5 (t, 2H), 3.11 (t, 2H).

5-chloro-7-bromo-2,3-dihydrobenzofuran (34)

To a stirred solution of (33) (1.84 g, 11.93 mmol) in acetic acid (10ml) at 0° C., was slowly added a solution of bromine (1.24 ml, 24 mmol)in acetic acid (5 ml). The reaction mixture was stirred at roomtemperature for 4.5 h. A 10% sodium thiosulphate solution (70 ml) wasadded and the mixture stirred for 10 min. The bulk of the solvent wasevaporated in vacuo. The resulting oil was dissolved in ether (50 ml),washed with water (20 ml), saturated NaHCO₂ (2×15 ml), brine (1×15 ml),dried Na₂ SO₄ and evaporated in vacuo to give 2.55 g (92%) of (34) as aoil.

¹ H-NMR (80 MHz, CDCl₃) δ 7.18 (s, 1H), 7.00 (s, 1H), 4.60 (t, 2H), 3.21(t, 2H).

2-pyridyl-[7-(5-chloro-2,3-dihydrobenzofuranyl)]ketone (35)

To a solution of 2-cyano-pyridine (3.53 ml, 36.24 mmol) in dry THF (15ml) at 0° C., was slowly added a solution of5-chloro-2,3-dihydrobenzofuranyl-7-magnesium bromide (≈32.95 mmol, madefrom (34) and Mg (921.1 mg) in dry THF) in dry THF (50 ml) maintainingthe temperature below 10° C. The resulting mixture was refluxed for 2 h.cooled to -5° C., 5N HCl (100 ml) was added and the mixture refluxed for2 h. The water/THF phase was extracted with ether (2×80 ml), neutralizedwith 5N NaOH (≈100 ml) and extracted with CH₂ Cl₂ (4×80 ml). Thecombined dried MgSO₄ and evaporated in vacuo, yielding (35) (6.04 g,71%) as green crystals. (35) was purified by chromatography (10% AcOEtin CH₂ Cl₂) yielding (35) 3.25 g (38%) as a orange solid.Recrystallization from EtOH gave a analytically pure sample.

Mp. 139°-140° C.

¹ H-NMR (80 MHz, CDCl₃) δ 8.63 (d, 1H), 8.03-7.23 (m, 5H), 4.55 (t, 2H),3.17 (t, 2H).

    ______________________________________                                        C.sub.14 H.sub.10 NClO.sub.2                                                              % C    % H        % N  % Cl                                       ______________________________________                                        Calculated  64.75  3.89       5.39 13.65                                      Found       64.68  3.94       5.32 13.69                                      ______________________________________                                    

Ethyl 2-pyridyl-[7-(5-chloro-2,3-dihydrobenzofuranyl)]acrylate (36)

(36) was prepared in a way similar to the one described for (9). (36)was isolated as a coloured oil, used without further purification. TLCon silica gel (AcOEt/Heptane 1:1) revealed two spots which were supposedto be the Z and E isomer of (36).

¹ H-NMR (80 MHz, CDCl₃) δ 8.58 (d, 1H), 7.57 (t, 1H), 7.11 (m, 4H), 6.87and 6.60 Z and E (2 s, 1H, C═CH), 4.53 (q, 2H), 4.02 (m, 2H), 3.17 (t,2H), 1.1 (q, 3H).

Ethyl 2-pyridyl-[7-(5-chloro-2,3-dihydrobenzofuranyl)]propionate (37)

(36) (6.84 g, 20.734 mmol) in dry EtOH (150 ml) was hydrogenated over10% Rh/C (1.5 g) catalyst at room temperature under atmosphericpressure. When H₂ absorption ceased the catalyst was filtered off andthe filtrate was concentrated in vacuo to give 6.32 g of a oil witch waspurified by chromatography (5% AcOEt in CH₂ Cl₂) yielding (37) 4.89 g(71%) as a oil.

¹ H-NMR (80 MHz, CDCl₃) δ 8.47 (d, 1H), 7.50 (t, 1H), 7.07 (m, 4H), 4.7(dd, 1H, CH--CH₂), 4.51 (t, 2H), 4.03 (q, 2H), 3.37 (dd, 1H, CH--CH₂),3.10 (t, 2H), 2.91 (dd, 1H, CH--CH₂), 1.10 (t, 3H).

2-[2-[7-(5-chloro-2,3-dihydrobenzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(38)

(38) was prepared in a way similar to the one described for (7). (3s)was purified by crystallization (acetone).

Mp. 150.5°-151.7° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.55 (d, 1H), 7.56 (dt, 1H), 7.22 (d, 1H),7.12 (t, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 4.69 (dd, 1H, CH--CH₂), 4.57(t, 2H), 3.58 (bs, 4H, CH₂ --CH₂), 3.27 (dd, 1H, CH--CH₂), 3.17 (t, 2H),2.89 (dd, 1H, CH--CH₂).

    ______________________________________                                        C.sub.18 H.sub.18 N.sub.3 ClO                                                             % C    % H        % N  % Cl                                       ______________________________________                                        Calculated  65.94  5.55       12.82                                                                              10.81                                      Found       65.88  5.64       12.51                                                                              10.80                                      ______________________________________                                    

EXAMPLE 10 Preparation of2-[2-[7-(5-methoxy-2-methyl-benzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline,(42), using preparation method F2-pyridyl-[7-(5-methoxy-2-methyl-benzofuranyl)]ketone (39)

To a stirred solution of 5-methoxy-2-methyl-benzofuran-7-carbonylchloride (4.36 g, 19.40 mmol) in dry DMF (40 ml) was added2-trimethylsilyl pyridine (2.94 ml, 19.40 mmol) and t-BuO⁻ K* (450 mg,4.01 mmol). The reaction mixture was stirred at room temperature for 48hours. The solvent was removed in vacuo and the residue dissolved in CH₂Cl₂ (100 ml) which was washed with water (3×40 ml), dried MgSO₄ andevaporated in vacuo yielding 5.43 g of a brown oil, >100%. Purificationof the oil was done by chromatography together with the crude productfrom the next example.

2-pyridyl-[7-(5-methoxy-2-methyl-benzofuranyl)]ketone (39)

To a stirred solution of 5-methoxy-2-methyl-benzofuran-7-carboxylic acidanhydride (8.57 g, 21.73 mmol) in dry DMF (80 ml) was added2-trimethylsilyl pyridine (1.64 g, 10.87 mmol) and t-BuO⁻ K* (225 mg,2.0 mmol). The reaction mixture was stirred at 100° C. for 28 hours. Thesolvent was removed in vacuo and the residue dissolved in CH₂ Cl₂ (180ml) which was washed with water (1×60 ml), saturated NaHCO₃ (2×60 ml),dried MgSO₄ and evaporated in vacuo yielding 7.46 g of a browncrystallinic mass which was extracted with EtOH. Evaporation of the EtOHin vacuo left crude (39) 4.17 g as a brown oil. Purification of thecombined oils by chromatography (5% AcOEt in CH₂ Cl₂) yielded 3.95 g of(39) as a green oil which on standing crystallized into long needles butin solution turned dark/black.

The compound was stored in the dark or used immediately. ¹ H-NMR (400MHz, d₆ -DMSO) δ 8.68 (d, 1H), 8.11 (t, 1H), 8.03 (d, 1H), 7.71 (dd,1H), 7.36 (d, 1H), 7.13 (d, 1H), 6.60 (s, 1H), 3.81 (s, 3H), 2.32 (s,3H).

Ethyl 2-pyridyl-[7-(5-methoxy-2-methyl-benzofuranyl)]acrylate (40)

(40) was prepared in a way similar to the one described for (9). (40)was isolated as a light coloured oil, used without further purification.

TLC on silica gel (AcOEt/Heptane 1:1) revealed two spots which weresupposed to be the Z and E isomer of (40).

¹ H-NMR (80 MHz, CDCl₃) δ 8.60 (d, 1H), 7.79-7.09 (m, 3H), 7.29 and 7.03(two s, 1H, Z and E methin), 6.89 (dd, 1H, H4 or H6 in Bf), 6.58 and6.33 (two dd, 1H, H4 or H6 in Bf), 6.26 (s, 1H), 4.05 (dq, 2H), 3.75 and3.65 (two s, 3H, OCH₃), 2.36 and 2.26 (two s, 3H).

Ethyl 3-[7-(5-methoxy-2-methyl-benzofuranyl)]-3-(2-pyridyl)propionate(41)

(41) was prepared in a way similar to the one described for (6). (41)was purified by chromatography (AcOEt/Heptane 1:1) yielding (41) as aoil.

¹ H-NMR (80 MHz, CDCl₃) δ 8.46 (d, 1H), 7.43 (t, 1H), 7.19 (s, 1H), 7.08(d, 1H), 6.93 (d, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 6.19 (s, 1H), 5.10(dd, 1H, CH--CH₂), 3.96 (q, 2H), 3.68 (s, 3H, OCH₃), 3.52 (dd, 1H,CH--CH₂), 2.98 (dd, 1H, CH--CH₂), 2.35 (s, 3H), 1.06 (t, 3H).

2-[2-[7-(5-methoxy-2-methyl-benzofuranyl)]-2-(2-pyridyl)ethyl]-2-imidazoline(42)

(42) was prepared in a way similar to the one described for (7). (42)was purified by recrystallization (acetone).

Mp. 144°-145° C.

¹ H-NMR (400 MHz, CDCl₃) δ 8.55 (d, 1H), 7,53 (dt, 1H), 7.27 (d, 1H),7.10 (dt, 1H), 6.78 (d, 1H), 6.71 (d, 1H), 6.28 (s, 1H), 5.06 (dd, 1H,CH--CH₂), 4.59 (bs, 1H, NH), 3.76 (s, 3H, OCH₃), 3.63 (bs, 2H, CH₂--CH₂), 3.43 (dd, 1H, CH--CH₂), 3.20 (bs, 2H), 3.03 (dd, 1H, CH--CH₂),2.42 (s, 3H, CH₃).

    ______________________________________                                        C.sub.20 H.sub.21 N.sub.3 O.sub.2                                                         % C          % H    % N                                           ______________________________________                                        Calculated  71.61        6.32   12.53                                         Found       71.64        6.43   12.31                                         ______________________________________                                    

We claim:
 1. A compound of the formula (I): ##STR10## wherein R¹ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or a bond tothe side chain carrying the imidazoline ring; R² is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or R² together with R³ representsan additional bond; R³ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl,C₁₋₄ alkoxy, phenyl, or phenyl substituted by a substituent selectedfrom the group consisting of fluoro, chloro, C₁₋₄ alkyl, and C₁₋₄ alkoxyor R³ together with R² represents an additional bond; R⁴ is hydrogen,fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl, or phenylsubstituted by a substituent selected from the group consisting offluoro, chloro, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁵ is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, phenyl, phenylsubstituted by a substituent selected from the group consisting ofmethyl, methoxy, fluoro and chloro, or a bond to the side chain carryingthe imidazoline ring; R⁶ is phenyl, phenyl substituted by a substituentselected from the group consisting methyl, methoxy, fluoro and chloro,or 2-pyridyl, 3-pyridyl, or 4-pyridyl, or 2-pyridyl, 3-pyridyl, or4-pyridyl, in which each pyridyl is substituted with a C₁₋₄ alkyl group;and R⁷ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, phenyl, phenyl substituted by a substituent selected from thegroup consisting of methyl, methoxy, fluoro and chloro, or a bond to theside chain carrying the imidazoline ring or a pharmaceuticallyacceptable acid addition salt thereof.
 2. The compound according toclaim 1 in which R¹ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, orC₁₋₄ alkoxy.
 3. The compound according to claim 1 in which R² ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, or C₁₋₄ alkoxy.
 4. Thecompound according to claim 1 in which R² together with R³ represents anadditional bond.
 5. The compound according to claim 1 in which R³ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl, orphenyl substituted by a substituent selected from the group consistingof fluoro, chloro, C₁₋₄ alkyl, and C₁₋₄ alkoxy.
 6. The compoundaccording to claim 1 in which R³ is phenyl substituted by a methylgroup.
 7. The compound according to claim 1 in which R³ is phenylsubstituted by a methoxy group.
 8. The compound according to claim 1 inwhich R⁴ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy,phenyl, or phenyl substituted by a substituent selected from the groupconsisting of fluoro, chloro, C₁₋₄ alkyl, and C₁₋₄ alkoxy.
 9. Thecompound according to claim 1 in which R⁴ is phenyl substituted by amethyl group.
 10. The compound according to claim 1 in which R⁴ isphenyl substituted by a methoxy group.
 11. The compound according toclaim 1 in which R⁵ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, phenyl, or phenyl substituted by a substituent selectedfrom the group consisting of fluoro, chloro, methyl, and methoxy. 12.The compound according to claim 1 in which each pyridyl is substitutedwith a methyl group.
 13. The compound according to claim 1 in which R⁷is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy,phenyl, or phenyl substituted by a substituent selected from the groupconsisting of fluoro, chloro, methyl, and methoxy.
 14. The compoundaccording to claim 1 in which R⁵ and R⁷ are independently hydrogen,fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, phenyl, orphenyl substituted by a substituent selected from the group consistingof fluoro, chloro, methyl, and methoxy.
 15. The compound according toclaim 1 in which R¹ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, orC₁₋₄ alkoxy and R⁷ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, phenyl, or phenyl substituted by a substituent selectedfrom the group consisting of fluoro, chloro, methyl, and methoxy. 16.The compound according to claim 1 in which R¹ is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl or C₁₋₄ alkoxy, and R⁵ is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl or C₁₋₄ alkoxy, hydroxy, phenyl, or phenylsubstituted by a substituent selected from the group consisting offluoro, chloro, methyl, and methoxy.
 17. A pharmaceutical compositionfor the treatment of type 2 diabetes comprising a compound of theformula (I): ##STR11## wherein R¹ is hydrogen, fluoro, chloro, bromo,C₁₋₄ alkyl, C₁₋₄ alkoxy or a bond to the side chain carrying theimidazoline ring; R¹ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl,C₁₋₄ alkoxy or R² together with R³ represents an additional bond; R³ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl, orphenyl substituted by a substituent selected from the group consistingof fluoro, chloro, C₁₋₄ alkyl, C₁₋₄ alkoxy or R³ together with R²represents an additional bond; R⁴ is hydrogen fluoro, chloro, bromo,C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl, or phenyl substituted by a substituentselected from the group consisting of fluoro, chloro, C₁₋₄ alkyl, C₁₋₄alkoxy; R⁵ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy,phenyl, hydroxy, or a bond to the side chain carrying the imidazolinering; R⁶ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; and R⁷ ishydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl,hydroxy, or a bond to the side chain carrying the imidazoline ring or apharmaceutically acceptable acid addition salt thereof.
 18. A method fortreating type 2 diabetes in a mammal comprising administering an amountof a compound of the formula (I): ##STR12## wherein R¹ is hydrogen,fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or a bond to the sidechain carrying the imidazoline ring; R² is hydrogen, fluoro, chloro,bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy or R² together with R³ represents anadditional bond; R³ is hydrogen, fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄alkoxy, phenyl, or phenyl substituted by a substituent selected from thegroup consisting of fluoro, chloro, C₁₋₄ alkyl, and C₁₋₄ alkoxy or R³together with R² represents an additional bond; R⁴ is hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, phenyl, or phenyl substituted bya substituent selected from the group consisting of fluoro, chloro, C₁₋₄alkyl, and C₁₋₄ alkoxy; R⁵ is hydrogen, fluoro, chloro, bromo, C₁₋₄alkyl, C₁₋₄ alkoxy, hydroxy, phenyl, phenyl substituted by a substituentselected from the group consisting of methyl, methoxy, fluoro andchloro, or a bond to the side chain carrying the imidazoline ring; R⁶ isphenyl, phenyl substituted by a substituent selected from the groupconsisting of methyl, methoxy, fluoro and chloro, or 2-pyridyl,3-pyridyl, or 4-pyridyl, or 2-pyridyl, 3-pyridyl, or 4-pyridyl, in whicheach pyridyl is substituted with a C₁₋₄ alkyl group; and R⁷ is hydrogen,fluoro, chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, phenyl, phenylsubstituted by a substituent selected from the group consisting ofmethyl, methoxy, fluoro and chloro, or a bond to the side chain carryingthe imidazoline ring or a pharmaceutically acceptable acid addition saltthereof, effective to decrease the blood glucose level of the mammal toa normal level.